Sanfilippo Syndrome B, also known as Mucopolysaccharidosis IIIB (MPSIIIB), is an autosomal recessive lysosomal storage disease (LSD) caused by mutations in the Naglu gene on human chromosome 7, which encodes a lysosomal enzyme known as N-acetyl-alpha-D-glucosaminidase (NaGlu). NaGlu is required for the degradation of heparan sulfate (HS) as part of the stepwise breakdown of glycosaminoglycans (GAG) in the lysosome. The deficiency or absence of NaGlu leads to accumulation and urinary excretion of heparan sulfate, resulting in severe central nervous system (CNS) abnormalities as well as mild systemic organ dysfunction; the effects on neurons in the CNS lead to delayed development, progressive mental retardation, neurological dysfunction, severe dementia, and early mortality. With over 70 different mutations identified to date, Sanfilippo Syndrome B exhibits extensive molecular and genetic heterogeneity.
The function of blood brain barrier (BBB) is to control cerebral homeostasis by selective transport of molecules and cells from the systemic compartment. The BBB is made up of structural components of the microvasculature endothelial cells of brain capillaries, epithelial cells of the choroids plexus, astrocytes end feet, and pericytes. Endothelial cells are connected via tight junction and adherens thereby forming a diffusion barrier.
Compromised blood-brain barrier (BBB) has been demonstrated in an animal model of MPSIIIB (Garbuzova-Davis et al., PLoS ONE 6(3): e16601 (2011)) as well as in human patients with MPSIIIA and MPSIIIC, closely related conditions that result from different enzyme deficiencies but that share the accumulation of HS and have common neuropathological manifestations (Garbuzova-Davis et al., BMC Neurology 13:174 (2013)). However, little is known about the condition of the BBB in MPS IIIB human patients.
This presents the problem of whether enzyme replacement therapy involving systemic delivery (e.g., intravenous administration) of recombinant human NaGlu enzyme which requires penetration of BBB in MPS IIIB patients can exert efficacy in the brain (CNS) as the disease is being treated and as a potential BBB dysfunction, if any, is being ameliorated. Therefore, a need exists for the safe and effective treatment of MPS IIIB from the systemic initial dosing to maintenance therapy in the CNS of MPS IIIB patients in accordance with their BBB structure and function as well as the kinetics of HS accumulation in the CNS that affects neurocognition and motor skills.